Studies of P-glycoprotein Drug Interactions - Administrative Supplement for Undergraduate Summer Research
P-糖蛋白药物相互作用的研究 - 本科生暑期研究行政补充
基本信息
- 批准号:10810072
- 负责人:
- 金额:$ 0.75万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-08-01 至 2026-04-30
- 项目状态:未结题
- 来源:
- 关键词:ABCB1 geneATP HydrolysisATP-Binding Cassette TransportersAccelerationAdministrative SupplementAffinityAmberAmino AcidsAntineoplastic AgentsAreaAromatic Amino AcidsBindingBinding SitesBiochemicalBiologicalBiological AssayBiological AvailabilityBiomedical EngineeringBlood - brain barrier anatomyCardiovascular AgentsCardiovascular systemCell membraneCellsChemicalsClinicalCodon NucleotidesCryoelectron MicroscopyCytoplasmCytoplasmic TailDevelopmentDimerizationDiseaseDocumentationDrug Binding SiteDrug CombinationsDrug DesignDrug EffluxDrug InteractionsDrug KineticsDrug Metabolic DetoxicationDrug MonitoringDrug TransportDrug resistanceDrug usageEnergy TransferEngineeringEnvironmentExcretory functionFluorescenceFluorescence SpectroscopyFluorescent ProbesFundingGoalsHIV/AIDSHydrophobicityIntestinesKidneyKineticsKnowledgeLaboratoriesLearningLigand BindingLipid BilayersLiverMapsMeasuresMembraneMental disordersMolecularMolecular ConformationMonitorMulti-Drug ResistanceNifedipineNucleotidesPaclitaxelPharmaceutical PreparationsPositioning AttributePrazosinPropertyPumpRecombinant ProteinsRhodamine 123Roentgen RaysScientistScreening procedureSiteStructureSurfaceSystemTechnologyTerminator CodonTertiary Protein StructureTestingTherapeuticToxinTransmembrane DomainTryptophanUnited States Food and Drug AdministrationVariantVinblastineX-Ray Crystallographyabsorptionbiophysical techniquescancer drug resistancecancer therapyclinically relevantcombatefflux pumpexperienceexperimental studyfunctional groupinhibitorinsightmolecular pumpnanodisknovel strategiesnovel therapeuticspreventprotein purificationprotein reconstitutionrational designreconstitutionsingle moleculesuccesssummer researchtooltryptophan analogundergraduate studentuptake
项目摘要
PROJECT SUMMARY/ABSTRACT (of the original funded project)
P-glycoprotein (Pgp) is a molecular pump that detoxifies cells by transporting hundreds of structurally unrelated
toxins out of the cell. Pgp limits uptake in the intestines, and enhances excretion of drugs in the liver, kidney and
blood-brain barrier, of many drugs that are used for treatment of cancers, HIV/AIDS, psychiatric illnesses, and
cardiovascular conditions. It is among the seven most important transporters responsible for regulating drug
absorption and disposition that now require documentation of drug interactions for approval of any new drugs by
the US Food and Drug Administration (FDA). Pgp is an ATP-binding cassette transporter with two
transmembrane domains (TMDs) and two nucleotide-binding domains (NBDs). It uses ATP hydrolysis to pump
substrates across the cell membranes. Our recent X-ray structures of Pgp identified hydrophobic and aromatic
amino acids that contribute to binding of different inhibitors to the drug-binding site. In this proposal, we will test
the hypothesis that therapeutic drugs bind to different subsets of residues within defined subpockets in the TMDs
of the protein. Our general approach is to introduce tryptophans (Trps) at strategic positions in order to monitor
drug binding. The Trps will be introduced on the background of a new fully functional Trp-less Pgp, or a low-Trp
Pgp that retains three native conformationally sensitive Trps in the cytoplasmic domains. Using fluorescence
changes, such as quenching, and resonance energy transfer (FRET), we will map out sites of interaction of the
purified protein with prototypical substrates that occupy biochemically defined and distinct binding sites, as well
as those of common therapeutic drugs and newly identified inhibitors. We will further insert a fluorescent Trp
analog (L-Anap) into wild-type Pgp using the amber stop codon suppression strategy to explore monitoring drug
binding in biological cell membranes. By determining how drugs and inhibitors modulate the cooperativity and
conformational dynamics of this multidomain transporter, we will gain unique insight into the mechanisms of drug
binding and their effects on Pgp function. With these new approaches, we will address the molecular mechanism
and kinetics of drug/inhibitor binding, determine synergistic effects, and refine the mechanisms of drug-drug
interactions in Pgp. The information will pave the way to new analytical approaches to refine Pgp drug interaction
studies of old and new drugs, and will be invaluable to redesign drugs with clinically favorable pharmacokinetics
and accelerate pharmacotherapeutic developments.
项目摘要/摘要(原资助项目)
项目成果
期刊论文数量(0)
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{{ truncateString('INA L URBATSCH', 18)}}的其他基金
Studies of P-glycoprotein Drug Interactions - Administrative Supplement for Equipment Purchase
P-糖蛋白药物相互作用研究-设备采购行政补充
- 批准号:
10795338 - 财政年份:2022
- 资助金额:
$ 0.75万 - 项目类别:
Understanding polyspecific drug binding in P-glycoprotein
了解 P-糖蛋白中的多特异性药物结合
- 批准号:
8365444 - 财政年份:2012
- 资助金额:
$ 0.75万 - 项目类别:
TransportPDB: Center for the X-ray Structure Determination of Human Transporters
TransportPDB:人类转运蛋白 X 射线结构测定中心
- 批准号:
8152921 - 财政年份:2010
- 资助金额:
$ 0.75万 - 项目类别:
TransportPDB: Center for the X-ray Structure Determination of Human Transporters
TransportPDB:人类转运蛋白 X 射线结构测定中心
- 批准号:
8715824 - 财政年份:
- 资助金额:
$ 0.75万 - 项目类别:
TransportPDB: Center for the X-ray Structure Determination of Human Transporters
TransportPDB:人类转运蛋白 X 射线结构测定中心
- 批准号:
8306892 - 财政年份:
- 资助金额:
$ 0.75万 - 项目类别:
TransportPDB: Center for the X-ray Structure Determination of Human Transporters
TransportPDB:人类转运蛋白 X 射线结构测定中心
- 批准号:
8534191 - 财政年份:
- 资助金额:
$ 0.75万 - 项目类别:
TransportPDB: Center for the X-ray Structure Determination of Human Transporters
TransportPDB:人类转运蛋白 X 射线结构测定中心
- 批准号:
8379742 - 财政年份:
- 资助金额:
$ 0.75万 - 项目类别:
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